World number one and defending champion Rafael Nadal will put his weary body on the line against a merciless Juan Martin del Potro on Friday with a place in the US Open final at stake.

Nadal, the three-time champion, faces 2009 winner Del Potro and is two wins from clinching an 18th Grand Slam title.

That would be just two behind Roger Federer and with an 11-5 career head-to-head advantage over the giant Argentine, he would usually be a comfortable favourite.

But this has been an unpredictable US Open with Federer knocked out by Australian world number 55 John Millman in the fourth round and Nadal coming close to joining his greatest rival at the exit door.

Whoever gets through Friday will have yet another major challenge on their hands in Sunday's final where either Novak Djokovic or Kei Nishikori will await.

The 32-year-old Nadal needed four hours and 49 minutes to get past Dominic Thiem 0-6, 6-4, 7-5, 6-7 (4/7), 7-6 (7/5) in an epic quarter-final which concluded at just after 2 a.m. on Wednesday.

Now, in his seventh semi-final at the US Open, Nadal is braced for another marathon with Del Potro, the third seed.

In July, Nadal came back from two sets to one down to beat Del Potro in the Wimbledon quarter-finals after four hours and 48 minutes.

A month earlier, Nadal had cruised past del Potro in straight sets in the semi-finals at Roland Garros on his way to an 11th title in Paris.

"It will be a very tough one. Juan Martin is a great player everywhere," said Nadal who will be playing in a seventh semi-fnal in New York.

"But the challenge of playing him on hard of course is even higher for me personally than playing against him on clay."

Nadal has been on court at this US Open just six minutes short of 16 hours.

He played back-to-back four-setters against Karen Khachanov and Nikoloz Basilashvili before recovering from breaks down in the third and fourth sets against Thiem.

11th semi-final for Djokovic

Del Potro has unleashed 66 aces and spent three and a half hours fewer on court than Nadal.

The 29-year-old is in his third semi-final at the US Open and sixth at the majors.

That figure would have been higher had he not missed 14 Grand Slams in his career due to a series of wrist surgeries.

"It could be another big battle just as at Wimbledon," said Del Potro.

"I like to play always with the No. 1 of the world, doesn't matter the tournament or the conditions or the weather."

Meanwhile, two-time US Open champion Djokovic will be playing in his 11th consecutive semi-final in New York, just two months after defying the odds to lift a 13th major at Wimbledon.

The 31-year-old Serb holds a 14-2 advantage over Nishikori including wins at Wimbledon and Rome this year.

However, one of Nishikori's wins came in the semi-finals in New York in 2014 when the Japanese star finished runner-up to Marin Cilic.

"When Kei is on, he's a top-five, top-10 player," said Djokovic.

"He has a great two-handed backhand, great footwork and is one of the quickest players on tour."

Djokovic needed two four-setters in his opening rounds but cruised through in straight sets against Richard Gasquet and John Millman.

He dropped serve just twice in the last two outings.

Nishikori, part of a history-making double act with Naomi Osaka in New York as the first Japanese man and woman to make the semi-finals of the same Slam, missed the 2017 US Open with a wrist injury.

The legacy of that also sidelined him until February "2014 will always be a good memory here. It was a tough battle and it will give me good confidence, even though I don't remember a lot of it," said the 28-year-old after getting revenge on Cilic in the quarter-finals.